The present invention relates generally to cyclin-dependent kinase II inhibitor compounds having utility as pharmacological agents for preventing/reducing the severity of epithelial cytotoxicity side effects of chemotherapy and/or radiation therapy, including alopecia plantar-palmar syndrome and/or mucositis. The invention also relates to a corresponding method of preventing/reducing the severity of such side effects, by administration of such a pharmalogical agent to a patient subjected to chemotherapy and/or radiation therapy treatment.
Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schiessinger and Ulirich, Neuron 1992, 9, 383. A partial non-limiting list of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-met, cRaf1, CSF1R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, JKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCxcex1, PKCxcex2, PKCxcex4, PKCxcex5, PKCxcex3, PKCxcex, PKCxcexc, PKCxcex6, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. Protein kineses have been implicated as targets in central nervous system disorders such as Alzheimer""s (Mandelkow, E. M. et al. FEBS Lett. 1992, 314, 315. Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167,99), pain sensation (Yashpal, K. J. Neurosci. 1995, 15, 3263-72), inflammatory disorders such as arthritis (Badger, J. Pharm. Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al. J. Cell Biol. 1991, 113, 857), and chronic obstructive pulmononary disease, bone diseases such as osteoporosis (Tanaka et al, Nature, 1996, 383, 528), cancer (Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), thrombosis (Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A. C. et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), blood vessel proliferative disorders such as angiogenesis (Strawn et al Cancer Res. 1996, 56, 3540; Jackson et al J. Pharm. Exp. Ther. 1998, 284, 687), restenosis (Buchdunger et al, Proc, Nat. Acad. Sci USA 1991, 92, 2258), autoimmune diseases and transplant rejection (Bolen and Brugge, Ann. Rev. Immunol. 1997, 15, 371) and infectious diseases such as viral (Littler, E. Nature 1992, 358, 160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335 A1 980212).
Chemotherapeutic techniques and radiation therapy techniques are well-established in the treatment of neoplastic conditions of various types. As concomitant side-effects to the administration of chemotherapy and/or radiation therapy, patients commonly experience severe host epithelial cell toxicity. The consequences of damage to the proliferating epithelium induced by chemotherapy frequently include hair loss (alopecia), plantar-palmar syndrome and mucositis; such side effects, especially mucositis, are also known to occur as a result of radiation therapy. These side-effects may be of varying severity, depending on the type, dosages and dosing schedule of the respective chemotherapy and/or radiation therapy involved.
The present invention provides a novel approach to preventing/reducing the severity of epithelial cytotoxicity side effects such as alopecia, plantar-palmar syndrome and/or mucositis in a subject receiving chermotherapy and/or radiation therapy, by administering to such subject an effective amount of a cyclin-dependent kinase II inhibitor.
A wide variety of particular cyclin-dependent kinase II inhibitor species useful in the broad practice of the present invention are hereinafter more fully described.
The cyclin-dependent kinase inhibitor is preferably non-systemically administered to the subject, more preferably topically.
The cyclin-dependent kinase II inhibitor may be administered topically to prevent/reduce the severity of alopecia incident to chemotherapy and/or radiation therapy, by application of the inhibitor compound, or a formulation containing same, to a corporeal locus susceptible to alopecia. For example, a topical formulation may be made up with the cyclin-dependent kinase II inhibitor present in an effective amount and such topical formulation may then be administered to the subject""s scalp and/or facial areas, to combat alopecia incident to chemotherapy and/or radiation therapy treatment.
For preventing/reducing the severity of plantar-palmar syndrome incident to chemotherapy and/or radiation therapy, the cyclin-dependent kinase II inhibitor may be topically administered to the plantar and/or palmar regions that are susceptible to lesioning as a concomitant condition of such therapeutic treatment.
In preventing/reducing the severity of mucositis as a, side effect incident to chemotherapeutic and/or radiation therapy treatment, the cyclin-dependent kinase II inhibitor is preferably administered topically to mouth and throat mucosa of the oral cavity.
In a combination therapeutic approach according to one embodiment of the invention, the patient receiving chemotherapy and/or radiation therapy may be contemporaneously administered the cyclin-dependent kinase II inhibitor in accordance with a selected dosage regimen that is effective to prevent/reduce the severity of two or more of the aforementioned side effects. Such administration is desirably of a non-systemic character, being topically applied to head regions susceptible to occurrence or progression of alopecia, being topically applied to plantar and/or palmar regions susceptible to the occurance or progression of plantar-palmar lesions, and/or being topically administered to oral cavity mucosa in the mouth and throat areas susceptible to occurrence or progression of mucositis.
The invention in another aspect relates to a cytoprotective composition for preventing/reducing the severity of epithelial cytotoxicity side effects incident to the administration of chemotherapy and/or radiation therapy, e.g., alopecia, plantar-palmar syndrome and/or mucositis. Such composition is suitably formulated to comprise an effective amount of a cyclin-dependent kinase II inhibitor for the prevention or reduction in the severity of the epithelial cytotoxicity side effects of the chemotherapy and/or radiation therapy. The composition may be formulated for such purpose with one or more pharmaceutically acceptable carriers, excipients or diluents.
Other aspects and features of the invention will be more fully apparent from the ensuing disclosure and appended claims.